The C-type lectins are widely expressed in cells of the immune system, including macrophages, B and T lymphocytes, mast cells, and natural killer (NK) cells. The characteristic structural feature conserved among members of this family of calcium-dependent lectins is an extracellular carbohydrate recognition domain. This domain consists of a series of invariant residues arranged in a characteristic pattern (Spiess, M (1990) Biochem 29:10009-10018). Receptor proteins of the C-type lectin superfamily do not generally share significant sequence homology beyond that of the carbohydrate recognition domain. For many of these proteins, there is no direct evidence for the binding of carbohydrates, and physiological ligands have not been identified. In fact, carbohydrate-binding activity has been inferred from the homology with the carbohydrate-binding domain of the asialoglycoprotein receptor (Spiess, supra).
Many C-type lectins are classified as Type II membrane proteins. The characteristic topology of the Type II membrane protein includes an extracellular C-terminus comprising the carbohydrate binding domain, an amino terminus facing the cytosol, and a membrane-spanning domain of approximately 20 apolar residues serving as the signal for membrane insertion. Several prolines generally precede the cytoplasmic side of the transmembrane domain. The prolines are suggested to prevent the steric interference of the amino-terminal domain with the transmembrane domain during membrane insertion. The N-terminal cytosolic domains of the C-type lectins are very diverse in both length and sequence. The cytosolic domains of most endocytotic receptors contain at least one tyrosine, which may be involved in signal transduction (Spiess, supra). Phosphorylation of the cytosolic tyrosine of the asialoglycoprotein receptor, a C-type lectin, has been demonstrated (Fallon RJ (1990) J Biol Chem 265: 3401-3406). The extracellular carbohydrate binding domains are readily separated from membrane-bound C-type lectin molecules by protease treatment. These isolated, soluble domains retain structural integrity and carbohydrate binding activity, owing in part to the three intrachain disulfide bonds present in the binding domains of this class of lectin.
Many cell surface receptor molecules expressed on macrophages belong to the C-type lectin supergene family. Macrophage lectin proteins perform a variety of functions in the recognition and destruction of foreign cells and pathogens.
Serotypes of Klebsiella pneumoniae have been shown to bind to macrophages via the interaction of K. pneumoniae surface mannose residues with mannose-specific lectins on the macrophage surface. Only the K. pneumoniae serotypes displaying certain surface mannose polysaccharide sequences bind to, and are subsequently internalized and destroyed by macrophages (Athamna A et al (1991) Infect Immun 59: 1673-1682).
A human macrophage C-type lectin has been found to recognize Tn Ag, a well-known human carcinoma-associated epitope (Suzki N et al (1996) J Immunol 156: 128-135). Unique macrophage lectins may specifically interact with surface antigens expressed by certain abnormal or diseased cells. The lectins may direct the macrophages to abnormal or diseased cells.
Binding of activated macrophages to mastocytoma cells was inhibited by pre-incubation of the macrophages with a glycopeptide inhibitor of a Gal/GalNAc-specific macrophage C-type lectin, as well as by the addition of anti-macrophage lectin antiserum. In addition, the anti-macrophage lectin antiserum inhibited the tumoricidal activity of the activated macrophages, suggesting that the binding of activated macrophages to these tumor cells through the Gal/GalNAc-specific macrophage lectin is an important part of the tumor cell killing mechanism (Oda S et al (1989) J Biochem (Tokyo) 105: 1040-1043). Furthermore, the recombinant cytosolic carbohydrate binding domain of the mouse macrophage C-type lectin also served as an inhibitor of cytotoxic activity, indicating that the lectin was a direct mediator of the macrophage tumoricidal response (Imai Y and Irimura T (1994) J Immunol Methods 171: 23-31).
Many diseases have been identified that relate to abnormalities of macrophage function, especially adherence, chemotaxis, and microbicidal activity. Some of these abnormalities may be due to defects in the recognition of foreign particles, diseased tissues or host tissues via lectin receptor molecules expressed by the macrophages. Other conditions derive from normal, yet undesirable, functioning of macrophages. Such undesirable conditions include graft and transplant rejection and pathogen colonization of host macrophages.
Increased expression of a macrophage cell-surface lectin was localized to inflammatory cells in rat cardiac allografts. Macrophage cell-surface lectins were proposed to be linked to the chronic rejection of cardiac allografts in arteriosclerosis. In this case the lectin served as a possible mediator of macrophage infiltration (Russel ME et al (1994) J Clin Invest 94: 722-730).
Pathogenic Mycobacteria, including M. tuberculosis, colonize activated macrophages. The attachment of such pathogens to macrophages is the preliminary step in pathogenesis. The colonization has been shown to occur via mannose-specific lectin receptors expressed on the macrophages (Goswami S et al (1994) FEBS Lett 355: 183-186).
Macrophage lectins clearly play an important role in the recognition and destruction of diseased and non-self cells. The selective modulation of the expression and specificity of a novel macrophage lectin may allow the successful management of diseases related to macrophage function, such as graft rejection or pathogen colonization, or the exploitation of the natural cytolytic capabilities of macrophages, such as specific targeting to tumors or infected host cells.